Recent studies of this laboratory have shown that the neurotoxicity of the venom of a rattlesnake (Crotalus dur. terr.), as measured by its capability to kill mice, is a cooperative phenomenon, involving a basic and an acidic protein. These usually form a tight complex which behaves as a single protein under most conditions, named crotoxin, when it was crystallized by Slotta and Fraenkel-Conrat in 1937 and characterized as such. The recent studies indicate that the basic component carries the typical hemolytic activity of crotoxin, presumably due to its formation of lysolecithin while no biological activity has as yet been found for the acidic protein, except that it activates the basic one to become "neurotoxic." We propose as a working hypothesis that the acidic protein shows a specific type of detergent-like action, possibly enabling the basic protein to enter neurons, attack membranes, and thereby exert its systemic toxicity. We plan (1) to establish whether the interaction must occur in vitro or whether the two proteins synergize when applied separately, (2) to attempt to replace the acidic protein with other polyanionic macromolecules, and with corresponding fractions obtained from other snake venoms, (3) to modify both in various ways which would increase or decrease their positively and negatively charged groups, (4) to search for simpler biological systems to replace the mouse-killing as a measure of neurotoxicity and to study the nature of this synergism in such a system, and (5) to evaluate this system as a tool for general neurobiological studies.